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Genetic Risk of Prion Disease Reevaluated, Thanks to Big Data

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Massive genetic databases collected by direct-to-consumer companies are helping scientists study rare conditions such as prion disease.| Flickr/ Kristie Wells

In 2011, a genetic test revealed that Sonia Minikel Vallabh carried a mutation associated with prion disease, the same disease that had claimed her mother's life. "Our first question was, what is the probability that Sonia will get this disease, given that she has the mutation?" said her husband Eric Vallabh Minikel.

Now, after leaving careers as a lawyer and an engineer, respectively, to become scientists, Vallabh and Minikel along with colleagues at the Broad Institute of Massachusetts Institute of Technology and Harvard have published a study in the 20 January issue of Science Translational Medicine that sheds new light on that question.

After crunching genetic data from more than 600,000 people, the researchers found that the genetic mutations underlying prion diseases differ greatly in how likely they are to cause the disease, ranging from harmful to relatively benign.

The findings may help genetic counselors more accurately predict disease risk for patients and their families and guide treatment strategies for prion diseases.

"There are a handful of people out there who have different mutations in the same gene…[and] had been told that they were at high risk of prion disease. Now, in light of our results, we can say that they are actually at pretty low risk," said Minikel. "That's a huge change."

More broadly, the study illustrates how patient activism and data sharing from genetic testing companies can accelerate advances in rare disease research.

Prion diseases are a group of rare, fatal, and incurable neurodegenerative disorders. The inherited form of the disease is caused by alterations in the prion protein (PRNP) gene that result in abnormal folding of the prion protein. Misfolded prions can trigger normal forms of the protein to also misfold, forming toxic clumps that damage the brain. Patients usually develop symptoms, such as dementia and difficulty moving, between the ages of 30 and 60, which lead to death several months to a few years later.

Sixty-three genetic variants of PRNP are suspected to cause prion disease. However, some individuals who harbor these mutations never develop the disease, complicating efforts to tease apart benign from harmful variants. The scant data available on rare conditions such as prion disease make it even more difficult to calculate the odds that a person carrying a mutation will actually develop the disease.

Taking advantage of recently available large-scale genomic databases, the researchers compared PRNP gene variants in 16,025 prion disease patients and a large comparison population. The latter group included data from 60,706 healthy individuals included in the Exome Aggregation Consortium, a collaborative effort by genetic researchers, and 531,575 customers of 23andMe Inc. who had opted to share their genomic data for research.

A direct-to-consumer genetic testing company, 23andMe Inc. analyzes customers' genetic make-up, including variants associated with rare genetic diseases. "They had exactly the type of data we needed," said Minikel. "It was really generous of them — and of all the customers who volunteered their data" for research.

The scientists confirmed that previously known rare variants that were detected only in prion disease patients clearly cause the disorder. However, other variants previously thought to cause prion disease were often found in healthy individuals, suggesting they are likely benign or confer only low risk for disease.

The researchers also identified three older individuals who carried only one working copy of the PRNP gene instead of two, but were completely healthy. This finding could mean that treatment strategies that block PRNP expression, which are currently under investigation, may be safer than previously thought. This "validation… gives us hope that therapies that lower prion protein levels could be well-tolerated," said Minikel.

Unfortunately, the study confirmed that Vallabh's genetic variant puts her at very high risk of developing prion disease, said Minikel, making the search for a treatment or cure all the more urgent.

"As always in science, these are baby steps — we're still years away from an effective treatment for these diseases — but I do think it's a step forward," he said.